Endothelin-1 (ET-1) is a 21 amino acid peptide isolated from the conditioned medium of cultured endothelial cells. Subsequent studies have shown it to be synthesised in endothelial cells, epithelial cells, and both vascular and non-vascular smooth muscle cells. It is the most potent vasoconstrictor agent ever identified, and causes vasoconstriction in most if not all vascular beds. Endothelin-1 has a number of other actions, including promoting smooth muscle mitogenesis, which may be of equal or greater importance in the underlying pathological processes of a variety of diseases (Hayes and Webb, 1998).
The acute actions of endothelin-1 in the airways and in the pulmonary vasculature include pulmonary arterial and venous vasoconstriction, extravasation and oedema formation, and bronchoconstriction. However, current evidence suggests that when expression of endothelin-1 is upregulated, its involvement in chronic changes may be just as important as any acute vasoconstrictor effect. This is particularly true for the pulmonary vasculature and airways where endothelin-1 may have a long-term role in remodeling by promoting vascular and tracheal smooth muscle mitogenesis, and stimulating collagen synthesis by pulmonary fibroblasts.
Current approaches to inhibiting ET-1 have focused mainly on development of antagonists but these may have systemic effects that are detrimental to the pulmonary circulation (e.g. peripheral hypotension). In addition there are at least two endothelin receptor subtypes—namely, endothelin-A (ETA) subtype and endothelin-B (ETB) subtype. Both appear to be involved in mediating the vasoconstrictor responses to endothelin in the pulmonary vasculature (McCulloch et al., 1998). But the endothelin-B subtype is also a clearance receptor so agents blocking it increase circulating ET-1 levels (Loffler et al., 1993, and Fukuroda et al., 1994) and may reduce the effectiveness of the antagonism.